Asymmetric Organocatalysis
Sarah Maifeld
September 19,2002
Approaches to Asymmetric Catalysis
Organometallic catalysis
– Broad scope
– Ligand control
– Inert conditions
– Cost and toxicity
Bioorganic catalysis
– Highly selective
– High rate of reaction
– Limited scope
Organocatalysis
Similar modes of action
– Lewis acidic/Lewis basic functionality
– Enzyme mimetics
Advantages
– Preparative
– Inexpensive
– Amenable to combinatorial approaches
History and Development
Early example
Bredig,G.; Fiske,P,S,Biochem,Z,1912,46,7,
Prelog,V.; Wilhelm,M,Helv,Chim,Acta 1954,37,1634,
H
O
H C N C N
O H
+
1 0 % e e
c a t a l y t i c
q u i n i n e
Applications
–Kinetic resolutions
–Phase transfer
catalysis
–Asymmetric synthesis
Outline
Cinchona Alkaloids
Proline
Amino Acid Derivatives
Peptide-like Catalysts
Heteroazolium Species
Cinchona Alkaloids
Enantiomeric b-hydroxyamine
functionality
Nucleophilic catalysts
Wynberg,H,Top,Stereochem,1986,16,87,
S
NH
N
O M e
O H
H
N
H
O HH
N
O M e
R
8 S,9 R - q u i n i n e 8 R,9 S - q u i n i d i n e
Asymmetric b-Lactones
Staring,E,G,J.; Wynberg,H,J,Am,Chem,Soc,1982,104,166.
Staring,E,G,J.; Wynberg,H,J,Org,Chem,1985,50,1977.
O
C l 3 C
H
O
H
H O
O
C l 3 C
+
1 - 2 m o l % q u i n i d i n e
t o l u e n e,- 2 5 ° C
8 9 % y i e l d
( S ) 9 8 % e e
Requires electron deficient aldehydes and aromatic ketones
68 – 98% yield
89 – 98% ee
Alkyl aryl ketones react in trace amounts
Aldol - Lactonization Mechanism
Dijkstra,G,D,H.; Kellog,R,M.; Wynberg,H.; Svendsen,J,S.; Marko,I.; Sharpless,K,B,
J,Am,Chem,Soc,1989,111,8069,
Cortez,G,S.; Tennyson,R,L.; Romo,D,J,Am,Chem,Soc,2001,123,7945.
N R
3
O
H H
O
N R
3
H
H
O
C C l
3
H
O
H
N R
3
O
C l
3
C
N R
3 O
O
C l
3
C
O
O
N R
3
C l
3
C
H
N
H
O A c
H
HN
O C H
3
O
+
*
*
*
*
A l d e h y d e a p p r o a c h e s t h e S i f a c e o f e n o l a t e
*
R e f a c e o f e n o l a t e b l o c k e d
Methyl Ketene Dimerization
Calter,M,A,J,Org,Chem,1996,61,8006.
O
B r
M e
B r
Z n
O
M e H
O
O
M e
M e
L i A l H
4
( S ) 9 3 % e e
( R ) 9 8 % e e
O
M e
M e
O H
O
R
3
N
M e
O
M e
1 m o l % a m i n e
T H F,- 7 8 ° C
*
*
q u i n i d i n e
( t r i m e t h y l s i l y l ) q u i n i n e
2 0 % y i e l d
*
*
Polypropionate Synthesis
Guo,X.; Liao,W.; Calter,M,A,Org,Lett,2001,3,1499.
O
M e
O
M e
N
M e O L i
O
M e H
M e
N
O
M e O
M e
O L i
M e
O
H
M e M e
O
O
M e
M e
M e M e M e M e
N
O
M e O
M e
O O H
M e
O H C
M e M e M e M e
s i p h o n a r i e n a l5 5 % y i e l d
T H F,- 7 8 ° C
T H F,- 7 8 ° C
T H F,- 7 8 ° C
0,3 m o l %
q u i n i d i n e
2
5 0 0 ° C
Asymmetric b-Lactams
O
C l
R
N M e
2
N M e
2
N
T s
C O
2
E tH
N
OT s
E t O
2
H
2
C R
O
R H
4 5 - 6 5 % y i e l d
9 9 / 1 c i s / t r a n s
9 6 - 9 9 % e e
R = a l k y l,a r y l,a l k o x y
1 0 m o l %
b e n z o y l q u i n i n e
( N R
3
* )
N R
3
*
O
* R
3
N
R
N R
3
* +
Taggi,A.E.; Hafez,A,M.; Wack,H.; Young,B.; Drury,W,J,III,Leckta,T,
J,Am,Chem,Soc,2000,122,7831.
Asymmetric Baylis-Hillman
Iwabuchi,Y.; Nakatani,M.; Yokoyama,N.; Hatakeyama,S,J,Am,Chem,Soc,1999,121,10219.
( R ) - 9 1 % e e
( R ) - 1 0 % e e
7 4 % y i e l d
5 8 % y i e l d
N
O
N
O M e
N
O
N
O H
H
O
O 2 N
O
O
C F 3
C F 3
O
O
C F 3
C F 3O H
O 2 N
+
1 h
D M F,- 5 0 ° C
1 0 m o l % c a t,
High enantioselectivities (91 – 99% ee)
Modest yields (31 – 58%)
Proline
Robinson Annulation
Intermolecular Aldol
Mannich Reaction
Michael Addition
Asymmetric Robinson Annulation
Eder,U.; Sauer,G.; Wiechert,R,Angew,Chem.,Int,Ed,1971,10,496,
Hajos,Z,G.; Parrish,D,R,J,Org,Chem,1974,39,1615,
O
O
M e
O
M e
P h H
M e
O
O
D M F
M e
O
O
O H
2 0 ° C,2 0 h
1 0 0 % y i e l d,9 3 % e e
p - T s O H
r e f l u x
3 m o l % L - P r o l i n e
L - P r o l i n e
N
H
C O
2
H
m e s o - t r i o n e
Proposed Mechanism
N
C O 2 -
O
O
H
N H
C O 2 -
N
3
H
R '
R
R ' '
O
H
( a l d o l a s e ) L y s
Enamine intermediate
Secondary amine and carboxylate essential
Second order in L-Proline Type I Aldolase
Puchot,C.; Sevestre,H.; Agami,C,Tetrahedron Lett,1986,27,1501.
Synthetic Applications
Mickus,D,E.; Rychnovsky,S,D,J,Org,Chem,1992,57,2732,
Danishefsky,S,et al,J,Am,Chem,Soc,1996,118,2843.
O
O
H O
Baccatin III
O
O
H O
A c O O O H
O
O A c
H
O B zH O
ent-Cholesterol
Direct Intermolecular Aldol
List,B.; Pojarliev,P.; Castello,C,J,Am,Chem,Soc,2001,3,573,
Notz,W.; List,B,J,Am,Chem,Soc,2000,122,7386,
List,B.; Lerner,R,A.; Barbas III,C,F,J,Am,Chem,Soc,2000,122,2395.
M e M e
O O
H
H
O
M e
O
O H
D M S O
D M S O
M e
O O H
M e
M e
M e
O O H
O H
9 7 % y i e l d
9 6 % e e
6 0 % y i e l d
> 2 0,1 d r
> 9 9 % e e
+
2 0 v o l %
2 0 v o l %
3 0 m o l % L - P r o l i n e
3 0 m o l % L - P r o l i n e+
Requires no preformed enolate
High concentration of ketone
Proline-Catalyzed Mechanism
Barbas III,C,F.;0 Lerner,R,A.; List,B,J,Am,Chem,Soc,2000,2395.
O
R
1
R
2
C H O
H
2
O
N
H
H O
O
N
O
O
O
R
2
H
H
R
1
- H
2
O
N
H
H O
O
N
-
O
O
R
1
R
2
OO H
R
1
R
2
N
O H
R
1
O
-
O
N
-
O
O
R
1
+
+
- H
+
Mannich Reaction
Pojarliev,P.; Biller,W,T.; Martin,H,J.; List,B.; J,Am,Chem,Soc,2002,124,827.
M e
O
O H
C H O
N O 2
O M e
N H 2
D M S O
M e
O
O H
H N
N O 2
O M e
9 2 % y i e l d
> 9 5 % d e
> 9 9 % e e
+
2 0 m o l % L - P r o l i n e
+
2 0 m o l %
M e M e
O O
H P h
O M e
N H 2
D M S O
M e
O H N
P h
O M e
+
2 0 m o l % L - P r o l i n e
+
8 0 % y i e l d
9 3 % e e2 0 m o l %
Good yields and high enantioselectivities with branched
and unbranched aldehydes
PMP group can be oxidatively removed
Opposite Enantiofacial Selectivity
Pojarliev,P.; Biller,W,T.; Martin,H,J.; List,B,J,Am,Chem,2002,124,827.
N
C O
2
H
X
R H
O
A r N H
2
H
N
M e O
N
X
R
O
H
O
N
X
O
O
R H
H
O
R
N H A r
X
O
R
O H
X
O
M a n n i c hA l d o l
+
) (
s y na n t i
)
(
a l d e h y d e
r e f a c e a t t a c k
i m i n e
s i f a c e a t t a c k
Michael Addition
Shiraishi,T.; Hirama,M.; Yamaguchi,M,J,Org,Chem,1996,61,3520.
O
N O 2 N H
H N
O
N O 2
+
3 - 7 m o l %
L - p r o l i n e
8 8 % y i e l d
9 3 % e e
O
C H 2 ( C O 2 i - P r ) 2
N
H
C O 2 R b O
C O 2 i - P r
C O 2 i - P r
9 1 % y i e l d
( R ) 5 9 % e e
5 m o l %
+
Pham,V.; Hanessian,S,Org,Lett,2000,2,2975.
Possible multicomponent catalyst
Amino Acid Derivatives
Diels-Alder Reaction
Strecker Reaction
Diels-Alder Reaction
o
N
O
O
M e+
1 0 m o l % c a t a l y s t
C H C l 3,- 2 5 ° C
N M e
O
O
H O-O
N
O
O
M e
H
N
R
R
R
O
H
*
Riant,O.; Kagan,H,B,Tetrahedron Lett,1989,52,7403.
A variety of chiral b-amino alcohols tested
High yields (85 – 95 %) but moderate ee’s (< 61%)
Diels Alder Reaction
O
H
N
N M e
M e
M eO
P h
H
H
N
N M e
M e
M eO
P h
C H O
+
8 2 % y i e l d
1,1 4 e x o,e n d o
9 4 % e e
2 0 m o l %
M e O H - H 2 O
H C l C l
-
O N
H
X Y
H C l N X
Y
Ahrendt,K,A.; Borths,C,J.; MacMillan,D,W,C,J,Am,Chem,Soc,2000,122,4243,
General Strategy,Formation of iminium ion to lower LUMO of dienophile
Highly enantioselective Diels-Alder catalyst
Stereocontrol
H
N
N M e
M e
M eO
R e f a c e b l o c k e d S i f a c e e x p o s e d
1,Formation of E-iminium isomer
2,Benzyl group hinders Re-face approach of diene
a,b-Unsaturated Ketones
M e M e
M e M e
E t
O
9 0 % y i e l d
2 0 0,1 e x o,e n d o
9 0 % e e
N
H
N
M eO
P h O
M e+
O
2 0 m o l % H C l O 4,E t O H
2 0 m o l %
Northrop,A,B.; MacMillan,D,W,C,J,Am,Chem,Soc,2002,124,2458,
General toward diene structure
Si face approach of diene
Favored cis-iminium isomer
N
N
M eO
P h O
M e
Strecker Reaction
Grogan,M,J.; Corey,E,J,Org,Lett,1999,157.
N
P h
P h
N
N N
H N
P h
P h
C N
H
1 0 m o l %
H C N,t o l u e n e
9 6 % y i e l d
( R ) 8 6 % e e
76 – 86% ee for aromatic imines
N-Benzhydryl group essential
H N
N
N H
H
NH
C
N Hydrogen bonding and van der Waals’
interactions
Peptide-based Catalysts
Hydrocyanation
Strecker Reaction
Azidation
Phosphorylation
Hydrocyanation
Oku,J.-I,J,Chem,Soc.,Chem,Commun,1981,229,
Tanaka,K.; Mori,A.; Inoue,S,J,Org,Chem,1990,55,181.
H N
N H
O
N
N
HO
c y c l o [ ( S ) - P h e n y l a l a n y l - ( S ) - h i s t i d y l ]
Designed as an oxynitrilase mimic
Acyclic structure showed no asymmetric induction
Mechanistic uncertainty
O
H
H C N
H
C NH O
2 m o l % c a t a l y s t
t o l u e n e,- 2 0 ° C
9 7 % c o n v e r s i o n
( R ) 9 7 % e e
Strecker Reaction
Iyer,M,S.; Gigstad,K,M.; Namdev,N,D.; Lipton,M,J,Am,Chem,Soc,1996,118,4910.
H
N
C H P h 2
H
P h 2 H C H N C N
2 m o l % c a t,H C N
M e O H,- 2 5 ° C
9 7 % y i e l d
( S ) > 9 9 % e e
+
( 2 e q )
H N
N H
O
R
O
N
H
N
H
N N H 2
N H
R =
R = n o a s y m m e t r i c i n d u c t i o n
m o d e s t t o h i g h s e l e c t i v i t y f o r
e l e c t r o n r i c h i m i n e s
Strecker Reaction
Sigman,M,S.; Jacobsen,E,N,J,Am,Chem,Soc,1998,120,4901,
Sigman,M,S.; Vachal,P.; Jacobsen,E,N,Angew,Chem.,Int,Ed,2000,39,1279.
H
N P h
H C N
2,T F A A
C N
N P hF 3 C
O
+
1,2 m o l % c a t,
t o l u e n e,- 7 0 ° C,2 0 h
9 6 % e e
8 8 % y i e l d
1,3 e q
O
R '
N
R
O
M
R ' '
O
N
H
N
H
N
H O
t - B u
N
O
O C O ( t - B u )
H
P h
Mechanistic Insights O
N
H
N
H
N
H O
t - B u
t - B u
N
O
O C O ( t - B u )
H
P h
Well-defined secondary structure
Z-Imine bridges both urea protons by hydrogen bonds
Vachal,P.; Jacobsen,E,N,J,Am,Chem,Soc,2002,124,10012.
Azidation
Guerin,D,J.; Miller,S,J,J,Am,Chem,Soc,2002,124,2134.
N
O
M e
O
T M S N
3
,t - B u C O
2
H
O
N
B O C N
N
N
P h
N
H
t - B u
H
N
O
M e
H
O
O
N
B O C N
N
N
P h
N
H
t - B u
H
N
O
M e
H
M e
O
N
O
M e
O N
3
2,5 m o l % c a t a l y t i c p e p t i d e
9 7 % y i e l d
6 3 % e e
9 5 % y i e l d
7 8 % e eb-turn unit
Methylation at the b-position of the histidine residue increased selectivity
Branching at g-carbon of substrate increased selectivity (up to 92% ee)
Phosphorylation
Sculimibrene,B,R.; Miller,S,J,J,Am,Chem,Soc,2001,123,10125.
OH N
H
N
N
N
P hO
H N
N H
O
P h
P h
P h
N H
O
M e
O
O M e
O
O
O
N
H
B O C
N
N
M e
O B n
O H
O HH O
B n O O B n
E t 3 N
C l - P = O ( O P h ) 2
O B n
O H
OH O
B n O O B n
P
O
O P h
O P h2 m o l % p e p t i d e
6 5 % y i e l d
> 9 8 % e e
1 0 % b i s p h o s p h o r y l a t i o n
t o l u e n e
Phosphorylation of histidine is the first step in a number
of signal transduction pathways
Heteroazolium Catalysts
Benzoin Condensation
Stetter Reaction
Thiamine Pyrophosphate
Coenzyme derived from vitamin B1
Important role in biochemical reactions
– Decarboxylation of a-keto acids
– Transfer of activated aldehyde groups
Thiazolium ring is key functionality
N
S
H 3 C
O
P
N
N
H 3 C
H 2 N O
O
O
P
O
O
O
t h i a m i n e p y r o p h o s p h a t e ( T P P )
Benzoin Condensation
Breslow,R,J,Am,Chem,Soc,1958,80,3719,
Schmuck,C.; Breslow,R,Tetrahedron Lett,1996,8241,
N
S
R
O H
P h
S
N
H
- H
+
- H
+
O
P h
P h
O H
N
S
R
N
S
R
O H
P h
O
P h H
N
S
H
R
O
P h H
H
+
N
S
R
P h
O H
H
N
S
R
P h
O H
P h
O H
- H
+
+
H
+
R
Asymmetric Attempts
Knight,R.; Leeper,F.J,Tetrahedron Lett,1997,38,3611,
Gerhard,A,U.; Leeper,F,J,Tetrahedron Lett,1997,38,3615,
Dvorak,C,A.; Rawal,V,H,Tetrahedron Lett,1998,39,2925.
B r
N
N
S
T s
N
O
O
P h
S
N
P h
O M s N
S
O
S i
t - B u
O T f
O
O H
P h
O
O H
P h
O
O H
P h
5 0 % y i e l d
2 1 % e e ( R )
1 0 0 % y i e l d
2 6 % e e ( S )
2 6 % y i e l d
2 7 % e e ( R )
2 0 m o l % c a t,
1 0 m o l % c a t,5 m o l % c a t,
Triazolium Catalysis
Breuer,K.; Enders,D,Helv,Chim,Acta,1996,79,1217.
O
H
H O
N
NN
O
O
C H 3
C H 3
P h
S i f a c e a p p r o a c h
y i e l d s r a n g e f r o m 2 2 - 7 2 %
e e ' s r a n g e f r o m 2 0 - 8 6 %
O
O
P h
N
N
N
P h
O
H
C l O 4
- O
O H
1,2 5 m o l %
K 2 C O 3,T H F 6 6 % y i e l d
7 5 % e e
Stetter Reaction
Breuer,K.; Runsink,J.; Enders,D,Helv,Chim,Acta,1996,79,1899.
C H O
O C O 2 M e O
O
P h
N
N
N
P h
C l O 4
-
O
O
C O 2 M e
K 2 C O 3,T H F
7 3 % y i e l d
( R ) 6 0 % e e
O
C O 2 M e
H O
N
NN
O
O
C H 3
C H 3
P h
Lower yields for substituted aryls
Moderate selectivity (41 – 71% ee)
Conclusion
Classic examples of asymmetric organocatalysis
– b-lactones
– Asymmetric Robinson Annulation
Direct aldol and Mannich reactions are
promising
Peptide catalysis offers unique opportunity for
further development
Complementary approach to organometallic
catalysis and bioorganic catalysis
.
Acknowledgements
Lee Group
Lisa Jungbauer
Terra Potocky
Rachel Weller
Susie Martins
Margaret Biddle
Marissa Rosen
Brian Lucas
Val Keller
Jodie Brice
Matthew Soellner
Shane Flickinger
Sarah Maifeld
September 19,2002
Approaches to Asymmetric Catalysis
Organometallic catalysis
– Broad scope
– Ligand control
– Inert conditions
– Cost and toxicity
Bioorganic catalysis
– Highly selective
– High rate of reaction
– Limited scope
Organocatalysis
Similar modes of action
– Lewis acidic/Lewis basic functionality
– Enzyme mimetics
Advantages
– Preparative
– Inexpensive
– Amenable to combinatorial approaches
History and Development
Early example
Bredig,G.; Fiske,P,S,Biochem,Z,1912,46,7,
Prelog,V.; Wilhelm,M,Helv,Chim,Acta 1954,37,1634,
H
O
H C N C N
O H
+
1 0 % e e
c a t a l y t i c
q u i n i n e
Applications
–Kinetic resolutions
–Phase transfer
catalysis
–Asymmetric synthesis
Outline
Cinchona Alkaloids
Proline
Amino Acid Derivatives
Peptide-like Catalysts
Heteroazolium Species
Cinchona Alkaloids
Enantiomeric b-hydroxyamine
functionality
Nucleophilic catalysts
Wynberg,H,Top,Stereochem,1986,16,87,
S
NH
N
O M e
O H
H
N
H
O HH
N
O M e
R
8 S,9 R - q u i n i n e 8 R,9 S - q u i n i d i n e
Asymmetric b-Lactones
Staring,E,G,J.; Wynberg,H,J,Am,Chem,Soc,1982,104,166.
Staring,E,G,J.; Wynberg,H,J,Org,Chem,1985,50,1977.
O
C l 3 C
H
O
H
H O
O
C l 3 C
+
1 - 2 m o l % q u i n i d i n e
t o l u e n e,- 2 5 ° C
8 9 % y i e l d
( S ) 9 8 % e e
Requires electron deficient aldehydes and aromatic ketones
68 – 98% yield
89 – 98% ee
Alkyl aryl ketones react in trace amounts
Aldol - Lactonization Mechanism
Dijkstra,G,D,H.; Kellog,R,M.; Wynberg,H.; Svendsen,J,S.; Marko,I.; Sharpless,K,B,
J,Am,Chem,Soc,1989,111,8069,
Cortez,G,S.; Tennyson,R,L.; Romo,D,J,Am,Chem,Soc,2001,123,7945.
N R
3
O
H H
O
N R
3
H
H
O
C C l
3
H
O
H
N R
3
O
C l
3
C
N R
3 O
O
C l
3
C
O
O
N R
3
C l
3
C
H
N
H
O A c
H
HN
O C H
3
O
+
*
*
*
*
A l d e h y d e a p p r o a c h e s t h e S i f a c e o f e n o l a t e
*
R e f a c e o f e n o l a t e b l o c k e d
Methyl Ketene Dimerization
Calter,M,A,J,Org,Chem,1996,61,8006.
O
B r
M e
B r
Z n
O
M e H
O
O
M e
M e
L i A l H
4
( S ) 9 3 % e e
( R ) 9 8 % e e
O
M e
M e
O H
O
R
3
N
M e
O
M e
1 m o l % a m i n e
T H F,- 7 8 ° C
*
*
q u i n i d i n e
( t r i m e t h y l s i l y l ) q u i n i n e
2 0 % y i e l d
*
*
Polypropionate Synthesis
Guo,X.; Liao,W.; Calter,M,A,Org,Lett,2001,3,1499.
O
M e
O
M e
N
M e O L i
O
M e H
M e
N
O
M e O
M e
O L i
M e
O
H
M e M e
O
O
M e
M e
M e M e M e M e
N
O
M e O
M e
O O H
M e
O H C
M e M e M e M e
s i p h o n a r i e n a l5 5 % y i e l d
T H F,- 7 8 ° C
T H F,- 7 8 ° C
T H F,- 7 8 ° C
0,3 m o l %
q u i n i d i n e
2
5 0 0 ° C
Asymmetric b-Lactams
O
C l
R
N M e
2
N M e
2
N
T s
C O
2
E tH
N
OT s
E t O
2
H
2
C R
O
R H
4 5 - 6 5 % y i e l d
9 9 / 1 c i s / t r a n s
9 6 - 9 9 % e e
R = a l k y l,a r y l,a l k o x y
1 0 m o l %
b e n z o y l q u i n i n e
( N R
3
* )
N R
3
*
O
* R
3
N
R
N R
3
* +
Taggi,A.E.; Hafez,A,M.; Wack,H.; Young,B.; Drury,W,J,III,Leckta,T,
J,Am,Chem,Soc,2000,122,7831.
Asymmetric Baylis-Hillman
Iwabuchi,Y.; Nakatani,M.; Yokoyama,N.; Hatakeyama,S,J,Am,Chem,Soc,1999,121,10219.
( R ) - 9 1 % e e
( R ) - 1 0 % e e
7 4 % y i e l d
5 8 % y i e l d
N
O
N
O M e
N
O
N
O H
H
O
O 2 N
O
O
C F 3
C F 3
O
O
C F 3
C F 3O H
O 2 N
+
1 h
D M F,- 5 0 ° C
1 0 m o l % c a t,
High enantioselectivities (91 – 99% ee)
Modest yields (31 – 58%)
Proline
Robinson Annulation
Intermolecular Aldol
Mannich Reaction
Michael Addition
Asymmetric Robinson Annulation
Eder,U.; Sauer,G.; Wiechert,R,Angew,Chem.,Int,Ed,1971,10,496,
Hajos,Z,G.; Parrish,D,R,J,Org,Chem,1974,39,1615,
O
O
M e
O
M e
P h H
M e
O
O
D M F
M e
O
O
O H
2 0 ° C,2 0 h
1 0 0 % y i e l d,9 3 % e e
p - T s O H
r e f l u x
3 m o l % L - P r o l i n e
L - P r o l i n e
N
H
C O
2
H
m e s o - t r i o n e
Proposed Mechanism
N
C O 2 -
O
O
H
N H
C O 2 -
N
3
H
R '
R
R ' '
O
H
( a l d o l a s e ) L y s
Enamine intermediate
Secondary amine and carboxylate essential
Second order in L-Proline Type I Aldolase
Puchot,C.; Sevestre,H.; Agami,C,Tetrahedron Lett,1986,27,1501.
Synthetic Applications
Mickus,D,E.; Rychnovsky,S,D,J,Org,Chem,1992,57,2732,
Danishefsky,S,et al,J,Am,Chem,Soc,1996,118,2843.
O
O
H O
Baccatin III
O
O
H O
A c O O O H
O
O A c
H
O B zH O
ent-Cholesterol
Direct Intermolecular Aldol
List,B.; Pojarliev,P.; Castello,C,J,Am,Chem,Soc,2001,3,573,
Notz,W.; List,B,J,Am,Chem,Soc,2000,122,7386,
List,B.; Lerner,R,A.; Barbas III,C,F,J,Am,Chem,Soc,2000,122,2395.
M e M e
O O
H
H
O
M e
O
O H
D M S O
D M S O
M e
O O H
M e
M e
M e
O O H
O H
9 7 % y i e l d
9 6 % e e
6 0 % y i e l d
> 2 0,1 d r
> 9 9 % e e
+
2 0 v o l %
2 0 v o l %
3 0 m o l % L - P r o l i n e
3 0 m o l % L - P r o l i n e+
Requires no preformed enolate
High concentration of ketone
Proline-Catalyzed Mechanism
Barbas III,C,F.;0 Lerner,R,A.; List,B,J,Am,Chem,Soc,2000,2395.
O
R
1
R
2
C H O
H
2
O
N
H
H O
O
N
O
O
O
R
2
H
H
R
1
- H
2
O
N
H
H O
O
N
-
O
O
R
1
R
2
OO H
R
1
R
2
N
O H
R
1
O
-
O
N
-
O
O
R
1
+
+
- H
+
Mannich Reaction
Pojarliev,P.; Biller,W,T.; Martin,H,J.; List,B.; J,Am,Chem,Soc,2002,124,827.
M e
O
O H
C H O
N O 2
O M e
N H 2
D M S O
M e
O
O H
H N
N O 2
O M e
9 2 % y i e l d
> 9 5 % d e
> 9 9 % e e
+
2 0 m o l % L - P r o l i n e
+
2 0 m o l %
M e M e
O O
H P h
O M e
N H 2
D M S O
M e
O H N
P h
O M e
+
2 0 m o l % L - P r o l i n e
+
8 0 % y i e l d
9 3 % e e2 0 m o l %
Good yields and high enantioselectivities with branched
and unbranched aldehydes
PMP group can be oxidatively removed
Opposite Enantiofacial Selectivity
Pojarliev,P.; Biller,W,T.; Martin,H,J.; List,B,J,Am,Chem,2002,124,827.
N
C O
2
H
X
R H
O
A r N H
2
H
N
M e O
N
X
R
O
H
O
N
X
O
O
R H
H
O
R
N H A r
X
O
R
O H
X
O
M a n n i c hA l d o l
+
) (
s y na n t i
)
(
a l d e h y d e
r e f a c e a t t a c k
i m i n e
s i f a c e a t t a c k
Michael Addition
Shiraishi,T.; Hirama,M.; Yamaguchi,M,J,Org,Chem,1996,61,3520.
O
N O 2 N H
H N
O
N O 2
+
3 - 7 m o l %
L - p r o l i n e
8 8 % y i e l d
9 3 % e e
O
C H 2 ( C O 2 i - P r ) 2
N
H
C O 2 R b O
C O 2 i - P r
C O 2 i - P r
9 1 % y i e l d
( R ) 5 9 % e e
5 m o l %
+
Pham,V.; Hanessian,S,Org,Lett,2000,2,2975.
Possible multicomponent catalyst
Amino Acid Derivatives
Diels-Alder Reaction
Strecker Reaction
Diels-Alder Reaction
o
N
O
O
M e+
1 0 m o l % c a t a l y s t
C H C l 3,- 2 5 ° C
N M e
O
O
H O-O
N
O
O
M e
H
N
R
R
R
O
H
*
Riant,O.; Kagan,H,B,Tetrahedron Lett,1989,52,7403.
A variety of chiral b-amino alcohols tested
High yields (85 – 95 %) but moderate ee’s (< 61%)
Diels Alder Reaction
O
H
N
N M e
M e
M eO
P h
H
H
N
N M e
M e
M eO
P h
C H O
+
8 2 % y i e l d
1,1 4 e x o,e n d o
9 4 % e e
2 0 m o l %
M e O H - H 2 O
H C l C l
-
O N
H
X Y
H C l N X
Y
Ahrendt,K,A.; Borths,C,J.; MacMillan,D,W,C,J,Am,Chem,Soc,2000,122,4243,
General Strategy,Formation of iminium ion to lower LUMO of dienophile
Highly enantioselective Diels-Alder catalyst
Stereocontrol
H
N
N M e
M e
M eO
R e f a c e b l o c k e d S i f a c e e x p o s e d
1,Formation of E-iminium isomer
2,Benzyl group hinders Re-face approach of diene
a,b-Unsaturated Ketones
M e M e
M e M e
E t
O
9 0 % y i e l d
2 0 0,1 e x o,e n d o
9 0 % e e
N
H
N
M eO
P h O
M e+
O
2 0 m o l % H C l O 4,E t O H
2 0 m o l %
Northrop,A,B.; MacMillan,D,W,C,J,Am,Chem,Soc,2002,124,2458,
General toward diene structure
Si face approach of diene
Favored cis-iminium isomer
N
N
M eO
P h O
M e
Strecker Reaction
Grogan,M,J.; Corey,E,J,Org,Lett,1999,157.
N
P h
P h
N
N N
H N
P h
P h
C N
H
1 0 m o l %
H C N,t o l u e n e
9 6 % y i e l d
( R ) 8 6 % e e
76 – 86% ee for aromatic imines
N-Benzhydryl group essential
H N
N
N H
H
NH
C
N Hydrogen bonding and van der Waals’
interactions
Peptide-based Catalysts
Hydrocyanation
Strecker Reaction
Azidation
Phosphorylation
Hydrocyanation
Oku,J.-I,J,Chem,Soc.,Chem,Commun,1981,229,
Tanaka,K.; Mori,A.; Inoue,S,J,Org,Chem,1990,55,181.
H N
N H
O
N
N
HO
c y c l o [ ( S ) - P h e n y l a l a n y l - ( S ) - h i s t i d y l ]
Designed as an oxynitrilase mimic
Acyclic structure showed no asymmetric induction
Mechanistic uncertainty
O
H
H C N
H
C NH O
2 m o l % c a t a l y s t
t o l u e n e,- 2 0 ° C
9 7 % c o n v e r s i o n
( R ) 9 7 % e e
Strecker Reaction
Iyer,M,S.; Gigstad,K,M.; Namdev,N,D.; Lipton,M,J,Am,Chem,Soc,1996,118,4910.
H
N
C H P h 2
H
P h 2 H C H N C N
2 m o l % c a t,H C N
M e O H,- 2 5 ° C
9 7 % y i e l d
( S ) > 9 9 % e e
+
( 2 e q )
H N
N H
O
R
O
N
H
N
H
N N H 2
N H
R =
R = n o a s y m m e t r i c i n d u c t i o n
m o d e s t t o h i g h s e l e c t i v i t y f o r
e l e c t r o n r i c h i m i n e s
Strecker Reaction
Sigman,M,S.; Jacobsen,E,N,J,Am,Chem,Soc,1998,120,4901,
Sigman,M,S.; Vachal,P.; Jacobsen,E,N,Angew,Chem.,Int,Ed,2000,39,1279.
H
N P h
H C N
2,T F A A
C N
N P hF 3 C
O
+
1,2 m o l % c a t,
t o l u e n e,- 7 0 ° C,2 0 h
9 6 % e e
8 8 % y i e l d
1,3 e q
O
R '
N
R
O
M
R ' '
O
N
H
N
H
N
H O
t - B u
N
O
O C O ( t - B u )
H
P h
Mechanistic Insights O
N
H
N
H
N
H O
t - B u
t - B u
N
O
O C O ( t - B u )
H
P h
Well-defined secondary structure
Z-Imine bridges both urea protons by hydrogen bonds
Vachal,P.; Jacobsen,E,N,J,Am,Chem,Soc,2002,124,10012.
Azidation
Guerin,D,J.; Miller,S,J,J,Am,Chem,Soc,2002,124,2134.
N
O
M e
O
T M S N
3
,t - B u C O
2
H
O
N
B O C N
N
N
P h
N
H
t - B u
H
N
O
M e
H
O
O
N
B O C N
N
N
P h
N
H
t - B u
H
N
O
M e
H
M e
O
N
O
M e
O N
3
2,5 m o l % c a t a l y t i c p e p t i d e
9 7 % y i e l d
6 3 % e e
9 5 % y i e l d
7 8 % e eb-turn unit
Methylation at the b-position of the histidine residue increased selectivity
Branching at g-carbon of substrate increased selectivity (up to 92% ee)
Phosphorylation
Sculimibrene,B,R.; Miller,S,J,J,Am,Chem,Soc,2001,123,10125.
OH N
H
N
N
N
P hO
H N
N H
O
P h
P h
P h
N H
O
M e
O
O M e
O
O
O
N
H
B O C
N
N
M e
O B n
O H
O HH O
B n O O B n
E t 3 N
C l - P = O ( O P h ) 2
O B n
O H
OH O
B n O O B n
P
O
O P h
O P h2 m o l % p e p t i d e
6 5 % y i e l d
> 9 8 % e e
1 0 % b i s p h o s p h o r y l a t i o n
t o l u e n e
Phosphorylation of histidine is the first step in a number
of signal transduction pathways
Heteroazolium Catalysts
Benzoin Condensation
Stetter Reaction
Thiamine Pyrophosphate
Coenzyme derived from vitamin B1
Important role in biochemical reactions
– Decarboxylation of a-keto acids
– Transfer of activated aldehyde groups
Thiazolium ring is key functionality
N
S
H 3 C
O
P
N
N
H 3 C
H 2 N O
O
O
P
O
O
O
t h i a m i n e p y r o p h o s p h a t e ( T P P )
Benzoin Condensation
Breslow,R,J,Am,Chem,Soc,1958,80,3719,
Schmuck,C.; Breslow,R,Tetrahedron Lett,1996,8241,
N
S
R
O H
P h
S
N
H
- H
+
- H
+
O
P h
P h
O H
N
S
R
N
S
R
O H
P h
O
P h H
N
S
H
R
O
P h H
H
+
N
S
R
P h
O H
H
N
S
R
P h
O H
P h
O H
- H
+
+
H
+
R
Asymmetric Attempts
Knight,R.; Leeper,F.J,Tetrahedron Lett,1997,38,3611,
Gerhard,A,U.; Leeper,F,J,Tetrahedron Lett,1997,38,3615,
Dvorak,C,A.; Rawal,V,H,Tetrahedron Lett,1998,39,2925.
B r
N
N
S
T s
N
O
O
P h
S
N
P h
O M s N
S
O
S i
t - B u
O T f
O
O H
P h
O
O H
P h
O
O H
P h
5 0 % y i e l d
2 1 % e e ( R )
1 0 0 % y i e l d
2 6 % e e ( S )
2 6 % y i e l d
2 7 % e e ( R )
2 0 m o l % c a t,
1 0 m o l % c a t,5 m o l % c a t,
Triazolium Catalysis
Breuer,K.; Enders,D,Helv,Chim,Acta,1996,79,1217.
O
H
H O
N
NN
O
O
C H 3
C H 3
P h
S i f a c e a p p r o a c h
y i e l d s r a n g e f r o m 2 2 - 7 2 %
e e ' s r a n g e f r o m 2 0 - 8 6 %
O
O
P h
N
N
N
P h
O
H
C l O 4
- O
O H
1,2 5 m o l %
K 2 C O 3,T H F 6 6 % y i e l d
7 5 % e e
Stetter Reaction
Breuer,K.; Runsink,J.; Enders,D,Helv,Chim,Acta,1996,79,1899.
C H O
O C O 2 M e O
O
P h
N
N
N
P h
C l O 4
-
O
O
C O 2 M e
K 2 C O 3,T H F
7 3 % y i e l d
( R ) 6 0 % e e
O
C O 2 M e
H O
N
NN
O
O
C H 3
C H 3
P h
Lower yields for substituted aryls
Moderate selectivity (41 – 71% ee)
Conclusion
Classic examples of asymmetric organocatalysis
– b-lactones
– Asymmetric Robinson Annulation
Direct aldol and Mannich reactions are
promising
Peptide catalysis offers unique opportunity for
further development
Complementary approach to organometallic
catalysis and bioorganic catalysis
.
Acknowledgements
Lee Group
Lisa Jungbauer
Terra Potocky
Rachel Weller
Susie Martins
Margaret Biddle
Marissa Rosen
Brian Lucas
Val Keller
Jodie Brice
Matthew Soellner
Shane Flickinger
